DE2906699A1 - OMEGA-HALOGENO-PGI LOW 2 -ANALOGS - Google Patents

Description

. - ". ■ ^.;.;.: I.vii« Al

Ν / 30822

REGISTRATION TEXT

Description!

(U-HALOGENO-PGI ₂ -ANALOGe

Applicant

ONO PHARMACEUTICAL CO. LTD.,

14 Doshomachi »2 ~ Chome, Higashi-ku,

Osaka 5 ^ 1 »Japan.

9098 3 6/0623

-X-

The present invention _{relates to new prostaglandin Ip analogs (PGI 2} analogs), a process for their production and pharmaceutical compositions containing them.

PGIp is a physiologically active natural substance with the following formula:

with the chemical name (5Z, 13E) - (9a, lla, 15S) -6,9-epoxyll, 15-dihydroxyprosta-5,13-dienoic acid [Nature, 263_, 663 (1976), Prostaglandins, 12, 685 (1976 ), loc. cit., 12, 915 (1976), loc. cit., 13_, 3 (1977), loc. cit., 13_, 375 (1977) and Chemical and Engineering News, December 20, 17 (1976)]. As is well known, PGIp can be generated by incubating prostaglandin G ₂ (PGG ₂ ) or prostaglandin H ₂ (PGH ₂ ) with microsome fractions prepared from the main or mesenteric artery of the pig, rabbit main artery or fundus uteri of the rat. PGI ₂ has a sagging effect on the artery that is specific to the artery and does not affect it

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/YES

the rest of the smooth muscles have “Furthermore, the platelet aggregation induced by arachidonic acid in humans is strongly inhibited _{by PGI 2.} . ·

If one takes into account that _{thromboxane A 2 produced by incubation of PGG 2} or PGH ₂ with platelet microsomes has a contracting effect on the artery and an aggregating effect on platelets, the above-mentioned properties of PGI _{2 show} that this is a very important one physiological role fulfilled in the living body »^^ 2 ^ ann ^ ^e ^ - ^ - ^he treatment of arteriosclerosis ,, cardiac insufficiency or thrombosis be useful.

Extensive investigations were carried out in order to find, among other things, new products which have the pharmacological properties of the "naturally occurring" PGI ₂ or one or more such properties to an increased extent or hitherto unknown pharmacological properties. Due to extensive research and experimentation work has now been found that the pharmacological properties of the "naturally occurring" PGI ₂ are improved or modified with respect to some of its effects when one of the hydrogen atoms at the end of the bound 15-position of the PGI ₂ n- Pentyl group and certain PGI ₂ analogs in which the n-penty group itself has been replaced by another alkyl group, which optionally includes a cycloalkyl ring, by a halogen atom

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replaced.

The present invention accordingly relates to new prostaglandin Ip analogs of the general formula:

[where Y for ethylene (ie -CHp-CHp-) or preferably trans-vinylene (ie ^ C = C ^ _n ), R ¹ for a hydrogen atom _{f is} a straight-chain or branched alkyl group having 1 to 12 and preferably 1 "to 4 carbon atoms , an aralkyl group with 7 to 12 carbon atoms, a cycloalkyl group with 4 to 7 carbon atoms optionally substituted by at least one straight-chain or branched alkyl group with 1 to 4 carbon atoms, one optionally with at least one chlorine atom or a trifluoromethyl group, straight-chain or branched alkyl group with 1 to 4 carbon atoms or phenyl group-substituted phenyl group, a -C _1n H _21n COOR group (where m is an integer from 1 to 12 and R is a straight-chain or branched alkyl group having 1 to 4 carbon atoms), a

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_n2n -Group (where η is an integer from 2 to 12 and

Rr is a hydrogen atom or a straight-chain or branched one Denotes an alkyl group having 1 to 4 carbon atoms) or a -CH-N ^ group (where η denotes the above

fi 7
Has meaning and R ° and R ^{1 can be} identical or different and each represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms), R for a methyl or ethyl group or preferably a hydrogen atom »X for a -C Hp group (where ρ is a is an integer from 2 to 8) or a -R - {. (CH, -,) group (where R is a

double bond or a straight-chain or branched alkylene group with 1 to 4 carbon atoms, R ^ a single bond or a straight-chain or branched alkylene group with 1 to 8 carbon atoms and q represents an integer from 3 to 6) and R ^ for a chlorine or Fluorine atom, the wavy line emanating from the carbon atoms in the 11- and 15-position denotes the α or ß configuration (ie S or R configuration) or mixed configuration and the double bond between C ₅ and Cg is Z] and cyclodextrin clathrates of such acids and esters and, if R is a hydrogen atom, their non-toxic salts (eg sodium salts) and, if R is a

p6 '67

-CH, -rßr group, in which n, R and R have the η tin \ given above. γ-?

Have meaning, their non-toxic acid addition salts. The hydroxyl groups bonded to the carbon atoms C = II and C-I5 in formula II preferably have

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the α configuration. It goes without saying that in the -R - (juJH ₂ ) _a group, R can be bonded to any carbon atom of the cycloalkyl ring, including the

Carbon atom (not shown) attached to R.

The present invention relates to all compounds of the general formula II in the "naturally occurring" form or the form enantiomeric thereto, or their Mixtures, especially in the racemic form, consisting of equimolar mixtures of the naturally occurring and the there is also enantiomeric form.

As those skilled in the art will readily recognize, the compounds represented by general formula II have at least five centers of chirality, which are located on the carbon atoms C-8, C-9, C-II, C-12 and C-15. Yet further centers of chirality can occur if R is a

8 9 branched alkyl group or C H »^ -H, C fL,, R or R are a branched alkylene group. It is well known that the existence of chirality leads to the existence of Isomerism. However, the compounds of the general formula II all have such a configuration that the in the side chains attached to the ring carbon atoms in the positions identified as 8 and 12 are in the trans position are to each other. Accordingly, all isomers of the general formula II and mixtures thereof, in which those Side chains in trans configuration on the ring carbon atoms are bound in the 8- and 12-position and the

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forms hydroxyl groups in 11- and Ifj-positions than to be considered falling within the scope of Formula II.

A straight or branched chain represented by R. An alkyl group with 1 to 12 carbon atoms is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, Heptyls, octyl, nonyl, decyl, undecyl and dodecyl or their Isomers.

An aralkyl group with 7 to 12 carbon atoms represented by R is, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl, 1- (2-naphthyl) ethyl and 2- (l-naphthyl) ethyl.

A represented by R, optionally by at least one straight-chain or branched alkyl group is-for example cycloalkyl group with 4 to 7 carbon atoms substituted with 1 to 4 carbon atoms Cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 2-methylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, Cyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 2,2-dimethylcyclopentyl, l-methyl-3-propylcyclopentyl, 2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclohexylj> 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert-butylcyclohexyl, 2,2-dimethylcyclohexyl, 2,6-dimethylcyclohexyl » 2,6-dimethyl-4-propylcyclohexyl and cycloheptyl.

One represented by R, optionally by

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-λί

at least one chlorine atom or one trifluoromethyl group, straight-chain or branched alkyl group with 1 to 4 carbon atoms or phenyl group substituted phenyl group is for example phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 4-ethylphenyl, 4-tert.-butylphenyl, 4-sec-butylphenyl, 3-trifluoromethylphenyl and 4-biphenyl.

Preferably R is a straight or branched chain alkyl group having 1 to 4 carbon atoms, e.g. Methyl.

A C _1n H ₂ J ₁₁ or C ^ H ^ portion of the C _1n H _21n COOR ^, C _n H _2n OR ⁵ - and ^ Η ^ Ν ^ γ groups represented by R is, for example, methylene (if m in the C ^ H ^ portion is 1), ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene and their isomers.

4 5 6 7

One represented by R, R, R and R, straight chain or branched alkyl group with 1 to 4 carbon atoms is, for example, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl and tert-butyl.

An alkylene group with 2 to 8 carbon atoms represented by CH ₂ is, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and their isomers.

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A group represented by Qp ^H ^ -X-CHp-R ^{is beis} Pi ^e l ^sweise l- (3-chloropropyl) -cyclo-R ⁹ -CH ₂ -R ³

butylj, l- (4-chlorot) utyl) -cyclo'butyl, l- (5-chloppentyl) -cyclobutyl, l-Co-chlorohexyl cyclobutyl ,. 2- (3-chloropropyl) -cyclobutyl, 3- (2-chloroethyl) -cyclobutyl, 3- (3-chloropropyl) -cyclobutylj, 3-chloromethylcyclopentyl, 3- (2-chloroethyl) -cyclopentylj, 3- (3-chloropropyl) -cyclopentyl, 3- (4-chlorobutyl) -cyclopentylj 3-chloromethylcyclopentylmethyl, 3- (2-chloroethyl) -cyclopentylmethyl, ^ Chloromethylcyclohexyl, 4- (2 ~ chloroethyl) -cyclohexyl, 4- (3-chloropropyl) -cyclohexyl, 3-chloromethylcyclohexylmethyl, 3- (2-chloroethyl) -cyclohexylmethylj 4-chloromethylcyclohexylmethyl, 4- (2-chloroethyl) -cyclohexylmethyl and the corresponding groups in which the chlorine atom is replaced by a fluorine atom; preferred are l- (4-fluorobutyl) -cyclobutyl and 3- (2-chloroethyl) -cyclopentyl. . ■

The symbol X preferably stands for a tetramethylene group, which is optionally replaced by a methyl group or a -R -u ^ CHp) group in which R is a simple one

Bond, q stands for 3 or 4 and R ^ for a straight-chain alkylene group with 1 to 3 carbon atoms, is substituted » ^:

According to a feature of the present invention, the prostaglandin Ip analogs of the general formula H ₅ in which the various symbols correspond to the above

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have the same meaning by dehydrohalogenation (i.e. dehydrobromination or dehydroCoding) of a compound the general formula:

OH X-CH - R

III

wherein R stands for a bromine or iodine atom, the absolute configurations at C, - and Cg (5S, 6S) or (5R, 6R) or a Mixture of these (5RS, 6RS) and the other symbols have the meaning given above.

The dehydrohalogenation can be done with a known Carry out dehydrohalogenating agents, for example (1) when R is a bromine atom, with a bicycloamine such as 1,5-diazabicyclo [5.4.0] undecene-5 (DBU), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN) or 1,4-diazabicyclo [2,2.2] octane (DABGO) or an alkali e.g. sodium or potassium alcoholate with 1 to 4 carbon atoms or (2), when R stands for an iodine atom, with a bicycloamine such as DBU, DBN or

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r a / L

DABCO or an alkali ζ.Β »sodium or potassium alcoholate with 1 to 4 carbon atoms, peroxide ₉ carbonate, hydroxide, benzoate, acetate, trifluoroacetate or bicarbonate or silver acetate or tetramethylammonium peroxide.

V Q

The reaction may range from room temperature to 110 C, preferably in the range from room temperature to 80 ⁰ C, and (I) -with a bicycloamine as a reagent optionally in the presence eines.inerten organic solvent, preferably in the absence of an inert organic solvent or in the presence of of toluene or benzene or (2), if the reagent is different from a bicycloamine, in the presence of an inert organic solvent, for example an alkanol with 1 to 4 carbon atoms such as methanol or ethanol or N, N-dimethylformamide.

Compounds of the general formula III, wherein the

various symbols have the meanings given above,

11 12

can be obtained by hydrolysis of the group OR and, if R of

12 is different to a hydrogen atom, the group OR in a compound of the general formula:

IV

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where R is a tetrahydropyranyl-2- or tetrahydrofuranyl-2 group, where these groups are each optionally substituted by at least one alkyl group,

12 or a 1-ethoxyethyl group and R for a hydrogen atom, a tetrahydropyranyl-2- or tetrahydrofuranyl-2 group, these groups in each case optionally through at least one alkyl group is substituted, or a 1-ethoxyethyl group, the absolute equations at C, - and Cg are (5R »6R) or (5S, 6S) or a mixture thereof and the other symbols have the meaning given above to produce a hydroxyl group.

Die.Gruppen OR ¹¹ and OR ¹² (if R ¹² is different from a hydrogen atom) in compounds of the general formula IV can be converted into hydroxyl groups by mild acid hydrolysis, (1) with the aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid or p-toluenesulfonic acid or the aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, advantageously in the presence of a water-miscible inert organic solvent, e.g. a lower alkanol such as methanol or ethanol, preferably methanol, or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran (preferably tetrahydrofuran), at a temperature ranging from room temperature to 75 ° C (preferably at a temperature ranging from room temperature to 45 ⁰ C) or (2) with the anhydrous solution of an organic acid such as p-toluenesulfonic acid or tri -

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fluoroacetic acid in a lower alkanol such as methanol or Ethanol in the temperature range from 10 ° to 45 ° C, useful mild acid hydrolysis can be done with a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture dilute hydrochloric acid and methanol, a mixture of acetic acid! Water and tetrahydrofuran, a mixture of phosphoric acid, Carry out water and tetrahydrofuran or a mixture of p-toluenesulfonic acid and methanol.

Compounds of the general formulas III and IV, i.e. compounds of the general formula:

(where R ■ * stands for a hydrogen atom, a tetrahydropyranyl-2- or tetrahydrofuranyl-2 group, these groups each optionally being substituted by at least one alkyl group, ”or a 1-ethoxyethyl group, the absolute configurations at Cj- and Cg (5R, 6R) or

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(5S, 6S) or a mixture thereof and the other symbols have the meaning given above), can be passed through Bromination or iodination and simultaneous ring closure of a compound of the general formula:

VI

in which the double bond between C ₁ - and Cg is cis and the other symbols have the meanings given above.

The conversion of a compound of the general formula VI into a compound of the general formula V can conveniently (1), if R in the compound of the formula V stands for a bromine atom, with N-bromosuccinimide or N-bromoacetamide in an aprotic organic solvent, for example methylene chloride , Chloroform, carbon tetrachloride, diethyl ether, N, N-dimethylformamide or tetrahydrofuran or a mixture of two or more of them, at a temperature of -30 ° to 70 ⁰ C or (2), if R ¹⁰ in the compound of formula V is a Iodine atom, with (i) iodine in pyridine, (ii) potassium periodate and potassium iodide in aqueous

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ger acetic acid, (iii) iodine and potassium iodide in the presence of alkali ™ eg sodium “or potassium carbonate or bicarbonate in water or (iv) iodine in the presence of alkali eg sodium ™ or potassium carbonate in an inert organic solvent eg methylene chloride or chloroform carried out in the range of from ⁰ ° C to room temperature. the product of general formula V so obtained is an isomer close mixing is, in which the absolute configurations at C ₅ and C ₆ (5R56R) and (5S, 6S), respectively. If desired, the mixture may be separated into the individual isomers by column, thin-layer or high-speed liquid chromatography over silica gel. Each isomer or the mixture of isomers can be converted into the desired PGIp analogs of the general formula II as described above, so that a separation of the isomers is unnecessary, unless one such separation is particularly desired.

The methods described above for the preparation of PGIp analogs of the general formula II can be identified by the absolute configurations at C ₁ - and Cg in formulas III and IV (5R, 6R) or (5S, 6S) or a mixture thereof and the double bond between C ₁ - and Cg in formula II is Z, represent the reaction sequence shown schematically.

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TABLE A

COOR

.10

0OR

(VI)

[-CH ₂ -R-

(if both R and R * represent hydrogen atoms stand)

.COOR

COOR

OH

(III)

(ID

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2S

The esters of the general formula III, V or VI, in which R is different from a hydrogen atom and the Other symbols have the meanings given above, are generalized by esterification of the corresponding acids Formula III, V or VI obtainable by methods known per se. Under the term "methods known per se", As applied in this patent, one understands methods hitherto used or in the chemical literature have been described. The esterification can, for example, if R is an alkyl group, using of (l) a diazoalkane, (2) an alkyl halide or (3) a Ν, Ν-dimethylformamide dialkyl acetal or, if R represents a group other than a hydrogen atom, (4) of dicyclohexylcarbodiimide (according to the in Applicant's Japanese Patent Publication No. 76/2305), (5) a pivaloyl halide (after that in British Patent No. 1,364,125 of the applicant described procedure) or (6) an arylsulfonyl or alkylsulfonyl halide (according to the in the Applicant's British Patent No. 1,362,965 Mode of operation).

The preparation of the ester using a diazoalkane is carried out by reacting the corresponding acid with an appropriate diazoalkane in an inert organic solvent such as diethyl ether, Essigester, methylene chloride or acetone, or a mixture of two or more thereof, in the range from -10 ⁰ C up to room temperature

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door, preferably at O ⁰ C, implemented. The esters are prepared using an alkyl halide by reacting the corresponding acid with a suitable alkyl halide, for example methyl iodide, (i) in acetone in the presence of an alkali metal carbonate, such as potassium carbonate [cf. J. Org. Chem., 3-4> 3717 (1967)], (ii) in Ν, Ν-dimethylacetamide or N, N-dimethylformamide in the presence of an alkali bicarbonate such as sodium or potassium bicarbonate [cf. Advan. Org. Chem., 5_, 37 (1965)] or (iii) in dimethyl sulfoxide in the presence of calcium oxide [cf. Synthesis, 262 (1972)]. When preparing the esters using an N, N-dimethylformamide dialkylacetal, the corresponding acid is reacted with an N, N-dimethylformamide dialkylacetal, for example N, N-dimethylformamide dimethylacetal, in anhydrous benzene [cf. HeIv. Chem. Acta. 48 "1746 (1965)]. The preparation of the esters using dicyclohexylcarbodiimide is carried out by reacting the corresponding acid with a suitable alcohol R OH, in which R is different from a hydrogen atom, in an inert organic solvent such as a halogenated hydrocarbon, for example chloroform or methylene chloride, in the presence of a Base such as pyridine or picoline, preferably pyridine, in the range from O ⁰ C to room temperature. The esters are prepared using a pivaloyl halide, arylsulfonyl halide or alkylsulfonyl halide by reacting the corresponding acid with a tertiary amine, for example triethylamine or

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2?

Pyridine »and a pivaloyl halide (e.g. pivaloyl chloride), Aryl sulfonyl halide (e.g., benzenesulfonyl chloride or p-toluenesulfonyl chloride) or alkylsulfonyl halide (e.g. Methanesulfonyl chloride or ethanesulfonyl chloride) in the presence or the absence of an inert organic solvent such as a halogenated hydrocarbon such as chloroform or methylene chloride, or diethyl ether for the preparation a mixed acid anhydride, which can be mixed in the range from O C to room temperature with a suitable Alcohol added. . .

The starting materials of the general formula VI can be prepared according to those in the following patent applications and patents methods described or their obvious modifications: British patent application No. 22 090/75, Belgian patent specification No. 842 113 and British patent application No. 29 756/78, as under the current Number 2 002 355A published.

In particular, starting materials of the general formula VI can be based on those in the above-mentioned patent applications synthetic routes described are prepared, using a compound of the general formula as the starting material:

R ¹⁴ OC-X-CH ₂ -OR ¹⁵ ·

14 1 '

wherein R represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms

15th
and R ^ for a hydrogen atom, a tetrahydropyranyl-2-

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or tetrahydrofuranyl-2-group, these groups respectively are optionally substituted by at least one alkyl group, or a 1-ethoxyethyl group and X has the meaning given above, is used.

The compounds of the general formula VII can be prepared by methods known per se.

For example, the connections of the general

14th
mean formula VII, in which R stands for a straight-chain or branched alkyl group with 1 to 4 carbon atoms and R ** for a tetrahydropyranyl-2- or tetrahydrofuranyl-2 group, these groups each optionally being substituted by at least one alkyl group, or a 1- Ethoxyethyl group and X has the meaning given above, with a lithium derivative of the formula:

CH-O O

^CH 3 °

to a compound of the general formula

CH-C) O jf-PH HP ¹⁶

3 \ t> \ X-CH ₂ -OR CH ₃ O O

(where R is a tetrahydropyranyl-2 or tetrahydrofuranyl-2 group, where these groups are each optionally substituted by at least one alkyl group, or

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a 1-ethoxyethyl group and X is the above "given Meaning), which with a compound of the general formula:

CHO

17th
(where R is an acetyl group or a p-phenylbenzoyl group) according to the reaction sequence shown schematically in Table B of British Patent Application No. 29 756/78, as published under No. 2 002 355A, to a compound of the general formula:

XI 16

X-GH ₂ -OR

in which the various symbols have the meanings given above, is implemented.

The compounds of the general formula XI can be converted into compounds of the general formula VI, in which R, R, R ¹² and R ^ each represent a hydrogen atom, according to the reaction sequence shown schematically in Table B below

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xand the other symbols have the meaning given above, convert. Appropriate reaction conditions for carrying out the reactions shown are in the two British and Belgian applications cited above or

TO

Patent specifications described. In panel B, R stands for an arylsulfonyl group, preferably p-toluenesulfonyl- or benzenesulfonyl group; the other symbols have the meanings given above, and the double bonds in Cc-Cg positions are ice.

TABLE B

XI

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TABLE B continued

GO ₂ H

XIV

VIA

OH

X-CH ₂ -R *

Esters of the prostaglandin Ip analog of the general Formula II, wherein R is a straight-chain or branched alkyl group having 1 to 12 carbon atoms and the Other symbols have the meaning given above, can be according to methods known per se by esterification of the

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the corresponding acid of general formula II, wherein R represents a hydrogen atom, prepared for example by reaction with the appropriate diazoalkane in an inert organic solvent, for example diethyl ether, Essigester, methylene chloride or acetone, or a mixture of two or more thereof, in the range of -10 C Ms room temperature and preferably at OC.

Cyclodextrin clathrates of the prostaglandin Ip analogues of the general formula II can be prepared by dissolving the cyclodextrin in water or a water-miscible organic solvent and adding the prostaglandin analogue to the solution in a water-miscible organic solvent. The mixture is then heated and the desired cyclodextrin clathrate product is isolated by concentrating the mixture under reduced pressure or by cooling and separating the product by filtration or pouring off. The organic solvent / water ratio can be varied depending on the solubility of the starting materials and products. Preferably, the temperature during the preparation of the cyclodextrin clathrates may 70 ⁰ C not exceed. In the preparation of the cyclodextrin clathrates, α-, β- or γ-cyclodextrin or mixtures thereof can be used. The conversion into cyclodextrin clathrates serves to increase the stability of the prostaglandin I ₂ analogs of the general formula II.

Compounds of the general formula II in which R

909836/0623. ι

stands for a hydrogen atom, one can, if desired convert into salts by methods known per se. Preferably these are non-toxic salts. Under the The term "non-toxic salts", as used in this patent specification, means salts, their cations (or in the case of the acid addition salts mentioned below, their anions) when used "in therapeutic doses relative are harmless to the animal organism, so that the-healing pharmacological properties of the compounds of the general formula II is not impaired by side effects attributable to those cations (or anions) will. The salts are preferably water-soluble. Suitable non-toxic salts are below among others the alkali e.g. sodium or potassium salts, alkaline earth e.g. calcium or magnesium salts as well as ammonium salts and pharmaceutically acceptable (i.e. non-toxic ^ Amine salts. Amines suitable for forming such salts with carboxylic acids are well known and include, for example theoretically by replacing one or more hydrogen atoms of ammonia with groups that are the same or can be different if more than one hydrogen atom is replaced, and which one, for example, under Alkyl groups having 1 to 6 carbon atoms and hydroxyalkyl groups with 2 to 3 carbon atoms selects derived amines. Suitable non-toxic amine salts are for example tetraalkylammonium such as tetramethylammonium salts and other organic amine salts such as methylamine salts,

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Dimethylamine salts, cyclopenty! Amine salts, benzy! Amine salts, Phenethylamine salts, piperidine salts, monoethanolamine salts, Diethanolamine salts, lysine salts or arginine salts.

The salts can be derived from the acids of the general formula II, in which R stands for a hydrogen atom methods known per se, for example by reacting stoichiometric amounts of an acid of the general formula II with the appropriate base, e.g. an alkali or alkaline earth hydroxide or carbonate, ammonium hydroxide, ammonia or an organic amine, in a suitable solvent. The salts can get through Lyophilization of the solution or, if they are sufficiently insoluble in the reaction medium, by filtration, if necessary after partial removal of the solvent, are isolated.

Sodium salts can also be prepared by an ester of the general formula II, in which R stands for an alkyl group with 1 to 12 carbon atoms and the other symbols have the meanings given above, with an equivalent amount of sodium hydroxide in the presence of an aqueous alkanol with 1 to 4 carbon atoms, preferably aqueous methanol, at a temperature of 0 ° to 60 ^Q C, preferably at room temperature, is reacted. Prostaglandin analogs of the general formula II,

^ 6

l 'R ^

wherein R represents a group - ^c _n ^H 2n ^N \ 7 ^{steepens "in the n" R}

7 ^

and R have the meaning given above, can according to methods known per se in preferably non-toxic

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see how acid addition salts convert above defined. Suitable acid addition salts are those with inorganic acids (such as hydrochlorides and sulfates) and with organic acids (such as acetates, propionates, succinates and benzoates) are formed.

The prostaglandin analog of the general formula II and their cyclodextrin clathrates and, if R stands for a hydrogen atom, their non-toxic salts and,

1 R ^ 6

if R is a group -CLH ₀ N ^ f ₇ , in which n, R

η £ 1x1 ^ S r> ι

and R have the meaning given above, their non-toxic acid addition salts have in a selective manner the valuable pharmacological properties typical of prostaglandins, especially those that lower blood pressure Effect, an inhibitory effect on platelet aggregation and a stimulatory effect on uterine contraction and are used to treat high blood pressure, peripheral circulatory disorders, and to prevent and treat brain thrombosis , Myocardial infarction and arteries ο sclerosis valuable.

For example, in standardized laboratory tests (i) with intravenous administration am with Allobarbital anesthetized dog with (5Z, 13E) - (9a, lla, 15S) -6,9-epoxy-11,15-dihydroxy-20-chloroprosta-5,13-dienoic acid methyl ester at a dose of 0.1 or 0.2 μg / kg body weight of the animal a 4 or 5 minute drop in blood pressure of 14 or 34 Torr, with (5Z, 13E) - (9a, lla, 15S, 16RS) -6,9-epoxy-ll, 15-dihydroxy-16-methyl- 20-chloroprosta-5 »13-dienoic acid methyl ester at a dose of 0.1 and 0.2, respectively

909836/0623

Oh

Body weight of the animal showed a drop in blood pressure of 20 and 48 torr lasting 11 and 15 minutes, respectively, with (5Z, 13E) - (9a, 11a, 15S, 17R) -6,9-epoxy-II, IS-dihydroxy-n-methyl ^ O-chloro- ■ prosta-5 »13-dienoic acid methyl ester in a dose of 100 μg / kg body weight of the animal a 3-minute drop in blood pressure by 10 Torr, with (5Ζ, 13Ε) - (9α, 11α, 15R) -6, 9-Epoxy-11,15-dihydroxy-15- [1- (4-fluorobutyl) -cyclobutyl] -16,17 »18,19,20-pentanorprosta-5,13-dienoic acid methyl ester in a dose of 1, 2 or 4 μg / kg body weight of the animal caused an 8, 20 or 15 minute drop in blood pressure by 24, 40 or 52 Torr and with (5Z, 13E) - (9a »Ha» 15S) -6,9-epoxy-II, 15 -dihydroxy-15- [3- (2-chloroethyl) cyclopentyl] -16,17,18,19> 20-pentanorprosta-5,13-dienoic acid methyl ester in a dose of 0.1, 0.2 and 0.4, respectively μg / kg body weight of the animal resulted in a 9 »11 or 15 minute drop in blood pressure by 22, 32 or 50 Torr, (ii) with (5Z, 13E) - (9a, 11a, 15ß) -6,9-epoxy-II , lS-dihydroxy ^ O-chloroprosta-5 »13-dienoic acid methyl ester, (5Z, 13E) - (9a, lla, 15S, 16RS) -6,9-Epoxy-ll, ^ -dihydroxy-Lö-methyl ^ O-chlorprcsta-5,13-dienoic acid emethyl ester, (5Z, 13E) - (9a »Ha , 15S, 17R) -6,9-epoxy-11,15-dihydroxy-17-methyl-20-chloroprosta-5 ₁ 13-dienoic acid methyl ester, (5Z, 13E) - (9a, 11a, 15R) -6.9 -Epoxy-ll, 15-dihydroxy-15- [1- (4-fluorobutyl) -cyclobutyl] -16,17,18,19,20-pentanorprosta-5 »13-dienoic acid methyl ester or (5Z, 13E) - (9a , Ha, 15S) -6,9-Epoxy-11,15-dihydroxy-15- [3- (2-chloroathy]) - cyclopentyl] -16,17,18,19,20-pentanorprosta-5,13- dienoic acid methyl ester compared to controls 50% inhibition of

909836/0623

Adenosine diphosphate-induced platelet aggregation in platelet-rich rat plasma at concentrations of 4.0. 10 ~ ³ , 1.5. 1O ^-3 , 3.3. 10 " ³ , 1.8. 10 ~ ² or 2.3. 10 ~ ³ μβ / ΐαΐ and (iii) with (5Z, 13E) - (9a, lla, 15S, l6RS) -6,9-epoxy- ll, lS-dihydroxy-Lö-methyl ^ O-chloroprosta-S> 13-dienoic acid methyl ester or (5Z, 13E) - (9a, lla, 15R) -6,9-epoxy-11,15-dihydroxy-l5- [ 1- (4-fluorobutyl) -cyclobutyl] -16,17,18, 19,20-pentanorpro sta-5 »13-dienoic acid methyl ester when administered intravenously at a dose of 10 or 10-20 μg / 4 cg body weight of the animal on the 20th On the day of gestation, stimulation of uterine contraction in the pregnant female rat.

The following PGIp analogs according to the invention are preferred: 18-chloro-19,20-dinor-PGI ₂ , Ig-chloro ^ O-nor-PGI ₂ , 20-chloro-PGI ₂ , 15-methyl-20-chloro-PGI ₂ , 16-methyl-20-chloro-PGI ₂ , 17-methyl-20-chloro-PGI ₂ , IS-methyl ^ O-chloro-PGI ₂ , 19 ~ methyl-20-chloro-PGI ₂ , 15, 16-dimethyl -20-chloro-PGI ₂ , 16, 16-dimethyl-20-chloro-PGI ₂ , 16, 17-dimethyl-20-chloro-PGI ₂ , 16,19-dimethyl-20-chloro-PGI ₂ , 16-ethyl -20-chloro-PGI ₂ , ^ -Aethyl ^ O-chloro-PGI ^ l6-propyl-20-chloro-PGI- ₂ , 17-propyl-20-chloro-PGI ₂ , 20-chloromethyl-PGI ₂ , 20- (2-chloroethyl) -PGI ₂ , 20- (3-chloropropyl) -PGI ₂ , - 20- (4-chlorobutyl) -PGI _£ , 15- [1- (3-chloropropyl) -cyclobutyl] -16,17, 18,19, ^ O-pentanor-PGIg, 15- [1- (4-chlorobutyl) -cyclobutyl] -16,17,18,19 , 20-pentanor-PGI ₂ , 15 - [! - (5-chloropentyl) -cyclobutyl] -16,17,18,19,20-pentanor-PGI ₂ , '^ - [! - (o-Chlorhexyli-cyclobutyll-löj ^ ilSag ^ O-pentanor-PGI ₂ , 15- (3-chloromethyl) cyclopentyl-16,17,18,19, 20

909836/0623 -

29Q6699

pentanor-PGI ₂ , 15- [3- (2-chloroethyl) -cyclopentyl] -16,17,18,19,20-pentanor-PGI ₂ , 15- [3- (3-chloropropyl) -cyclopentyl] -16, 17,18,19,20-pentanor PGI ₂ , 15- [3- (4-chlorobutyl) cyclopentyl] -16,17,18,19,20-Pe ^ aHOr PGI ₂ , 15- (3-chloromethyl ) -cyclohexyl-16,17,18,19,20-pentanor-PGI ₂ , 15- [3- (2-chloroethyl) -cyclohexyl] -16,17,18,19,20-pentanor-PGI ₂ , 15- [3- (3-chloropropyl) cyclohexyl] -16,17,18,19,20-pentanor PGI ₂ , 15- [3- (4-chlorobutyl) cyclohexyl] -16,17,18,19.20 -pentanor-PGI ₂ , the corresponding compounds in which the chlorine atom is replaced by fluorine, and 13,14-dihydro analogs, esters, cyclodextrin clathrates and non-toxic salts of such chlorine and fluorine compounds.

Particularly preferred PGI ₂ ~ analogs according to the invention are (5Z, 13E) - (9a, 11a, 15S, 16RS) -6,9-epoxy-11, 15-dihydroxyl6-methyl-20-chloroprosta-5,13-dienoic acid methyl ester, (5Z , 15E) - (9a, lla, 15R) -6,9-epoxy-II _f 15-dihydro3 {y-15- [1- (4-f-fluorobutyl) -cyclobutyl] -16,17,18,19,20 -pentanorprosta-5,13-dienoic acid methyl ester, (5Z, 13E) - (9a, lla, 15S, l7R) -6,9-epoxy-11,15-dihydroxy-17-methyl-20-chlorpr ο s ta-5, 13-dienoic acid methyl ester, (5Z, 13E) - (9a, lla, 15S) -6,9-epoxy-II, 15rdihydroxy-15- [3- (2-chloroethyl) -cyclopentyl] -16,17,18, 19 , 20- pentanorprosta-5,13-dienoic acid methyl ester and (5Z, 13E) - (9a, 11a, 15S) -6,9-epoxy-ll, 15-dihydroxy-20-chloroprosta-5,13-dienoic acid methyl ester.

909836/0623

The following reference examples and examples explain the production of the prostaglandin 12 analogs according to the invention. "DSC", "IR" and "NMI" stand for "thin layer chromatography", "infrared absorption spectrum" or "nuclear magnetic resonance spectrum". Where solvent ratios are given, e.g. at chromatographic separations, these are volume ratios.

REFERENCE EXAMPLE 1

(5Z, 15E) - (9K> lla, 15R) -9, ll, 15-trihydroxy-15-ri- (4-fluorobutyl) cyclobutyl1-16 , 17th > 18,19,20-pentanorprosta-5,15-dienoic acid methyl ester

The solution of 1.4 g of (5Ζ, 13Ε) - (9α »11α> 15R) -9» hydroxy-ll, 15-bis-tetrahydropyranyl-2'-oxy-15- [l- (4-fluorobutyl) -cyclobutyl] -16,17,18,19 »20-pentanorprosta-5> 13-dienoic acid methyl ester [prepared according to example 10 of British patent application No. 29 756/78 (published under serial no. 2 002 355 A)] in 3 ml of tetrahydrofuran with 15 ml of 65% by volume aqueous acetic acid solution. The mixture is stirred for 3 hours at 5O ⁰ C and then concentrated under reduced pressure to an oily product that contains acetic acid which is removed azeotropically under reduced pressure with toluene. The residue obtained is purified by column chromatography over silica gel using cyclohexane / ethyl acetate (1: 1) as the eluent, 645 mg of the title compound having the following physical characteristics being obtained:

909836/0623

DSC (mobile phase ethyl acetate): Rf = 0.26; IR (liquid film): ν = 2950, 2880 and 1745 cm "¹; NMR (CDCl ₃ -LoSUiIg): δ = 5 * 66-5.30 (4H, m), 4.70 (IH, t),

4.3-3.8 (4H, m) and 3.67 (3H, s).

EXAMPLE 1

(13E) - (5RS, 6RS, 9g, 11 cc, 15S, l6RS) -5-iodine-6,9-epoxv-ll, 15- dihydroxv-16-methvl-20-chloroprost-13-enoic acid methyl ester

The solution of 140 mg (5Z, 13E) - (9a, 11a, 15S, 16RS) -9, 11, 15-trihydroxy-16-methyl-20-chloroprosta-5,13-dienoic acid methyl ester [according to Example 8] is added under nitrogen British patent application No. 22 090/75 and eg the equivalent Belgian patent specification No. 842 113] in 5 ml of methylene chloride with 194 mg of anhydrous potassium carbonate. 200 mg of iodine are added in portions to the reaction mixture over the course of 2 hours at 0 ^{° C. with stirring.} It is diluted with diethyl ether, washed with aqueous sodium thiosulfate solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over silica gel using cyclohexane / ethyl acetate (2: 1) as the eluant, with 135 mg of the title compound with the following physical characteristics:

DSC (mobile phase chloroform / tetrahydrofuran / acetic acid = 10: 2: 1): Rf = 0.44;
IR (liquid film): ν = 3400, 1740, Ι44θ, 1250 and 970 cm ¹ ;

909836/0623

NMR (CDCl ^ solution): δ = 5 »7-5ι4 (2Η, m), 4.7-4.4 (IH, m), 4.25-3.7 (4Η, m), 3.68 (3H, s), 3.55 (2H, t) and 1.0-0.7 (3H, m). '"

The following connections are made using the same procedure as described above.

(a) (13E) - (5RS, 6RS, 9a, 11a, 15R) -5-iodo-6,9-epoxy-11,15-dihydroxy-15- [1- (4-fluorobutyl) -cyclobutyl] -I6 , 17 »18.19» 20-pentanorprost-13-enoic acid methyl ester with the following physical characteristics is obtained from (5Z, 13E) - (9a, Ila, 15R) -9, H, 15-trihydroxy-15- [1- (4-fluorobutyl) -cyclobutyl] -16.17, 18,19,20-pentanorprosta-5,13-dienoic acid methyl ester manufactured.

DSC (mobile phase ethyl acetate): Rf = 0.39;

IR (liquid film): ν = 2950, 2880 and 1745 cm "¹; EMR (CDC1 ₃ solution): δ = 5.63-5.33 (2H, m), 5.0-4.3 (3H, m)

and 3.57 (3H, s).

(b) (l3E) - (5RS, 6RS, 9a, lla, 15S, 17R) -5-iodo-6,9-epoxy-11, IS-dihydroxy - ^ - methyl ^ O-chloroprost - ^ - enoic acid methyl ester With the following physical characteristics, (5Z, 13E) - (9α, 11α, 15S, 17R) -9,11, IS-trihydraxy-rZ-methyl-20-chloroprosta-5,13-dienoic acid methyl ester manufactured:

IR (liquid film): ν = 3500 and 3400 cm ""¹; NMR (CDCl ^ solution): δ = 5.63-5.43 (2H, m), 4.55 (IH, m),

4.10 (2H, m), 3.68 (3H, s), 3.53 (2H, - / t) and 0.94 (3H, d).

(c) (13E) - (5RS, 6RS, 9a, llct, 15S) -5-iodo-6,9-epoxy-11 _f 15-dihydroxy-15- [3- (2-chloroethyl) cyclopentyl] - 16 , 17,18,19,20-pentanorprost-13-enoic acid methyl ester with

909836/062 3

The following physical characteristics are derived from (5Z, 13E) - (9a, lla, 15S) -9, ll, 15-trihydroxy-15- [3- (2-chloroethyl) - cyclopentyl] -16,17,18,19,20-pentanorprosta-5,13-dienoic acid

methyl ester produced:,.

DSC (mobile phase ethyl acetate): Rf = 0.38; IR (liquid film): ν = 3400, 1740 and 975 cm "¹; NMR (CDC1 ₃ solution): δ = 5 * 65-5.4 (2H, m), 4.7-4.4 (IH, m),

4.2-3.3 (6H, m) and 3.67 (3H, s).

EXAMPLE 2

(5Z, 13E) - (9a _> -lla, 15S, 16RS) -6,9-Epoxv-ll, 15-dihvdroxv 16-methyl-20-chloroprosta-5-13-dienoic acid methyl ester

The solution of 116 mg prepared according to Example 1 (13E) - (5RS, 6RS, 9a, lla, 15 £ _? ___ 16RS) -5-iodine-6,9-epoxy-ll, lS-dihydroxy- is stirred under nitrogen. Lö-methyl ^ O-chloroprost-13-enoic acid methyl ester and 0.4 ml of 1,5-diazabicyclo [5.4.0] undecene-5 (DBU) for 18 hours at room temperature and then cooled to ⁰ ° C. The reaction mixture is admixed with 2 ml of 1N hydrochloric acid and 2 ml of phosphate buffer solution (pH 6.86) ^{while cooling to 0 ° C.} Extract quickly with diethyl ether, dry the extract over anhydrous magnesium sulfate, concentrate under reduced pressure and purify the residue by column chromatography over Florisil (an activated magnesium silicate; "Florisil" is a registered trademark of Florin Co.) using 0.1% Triethylamine-containing ethyl acetate / n-hexane (1: 1) as the eluent, 52 mg of the

909836/0623

Title compound with the following physical characteristics is given:

DSC (mobile phase diethyl ether / acetone = 3: 1 with 0.1 % triethylamine, using a silica gel plate pretreated with 5% by volume triethylamine solution in diethyl ether): Rf = 0.52;

IR (chloroform solution): ν = 3400, 1730, 1700 and 970 cm "¹; NMR (CDCl ₃ - + benzene solution): δ = 5.7-5.4 (2H, m), 4.7-4.4

(IH, m), 4.3-3.6 (3H, m), 3.65 (3H, s), 3.53 (2H, t) and

1.0-0.7 (3H, m). '

The following connections are made using the same procedure as described above.

(ä) (5Z, 13E) - (9a, IIIa, 15R) -6,9-epoxy-II, 15-dihydroxy-15- [1- (4-fluorobutyl) -cyclobutyl] -16,17,18,19 , 20-pentanorprosta-5 »13-dienoic acid methyl ester 1 15- [1- (4-fluorobutyl) -cyclobutyl] -16,17,18,19,20-pentanor-PGI ₂ -methyles tevj with the following physical characteristics is' from according to Example 1 (a) obtained (13E) - (5RS, 6RS, 9a, IIIa, 15R) -5-iodo-6,9-epoxy-II, 15-dihydroxy-15- [1- (4-fluorobutyl) -cyclobutyl ] -16,17,18,19,20-pentanorprost-l3-enoic acid methyl ester produced:

DSC (mobile phase ethyl acetate with 0.1% triethylamine, using a silica gel plate pretreated with 5% triethylamine solution in diethyl ether): Rf = 0.40; IR (liquid film): ν = 2950, 2870, 1740, 1700, 1440 and 1380 cm "¹;
NMR (CCl ₄ solution): δ = 5.51 (2H, t), 4.62 (IH, t),

9 0 9836/0623

29061699

• 4.05 (IH, t), 4.7-3.2 (6H, m) and 3.63 (3H, s).

(b) (5Z, 13E) - (9a, IIIa, 15S, 17R) -6,9-epoxy-II, 15-dihydroxy-17-methyl-20-chloroprosta-5,13-dienoic acid methyl ester (17R-methyl-20 -chlor-PGI ₂ -methylester) with the following physical characteristics is obtained from (13E) - (5RS, 6RS, 9a, 11a, 15S, 17R) -5-iodine-6,9-epoxy-! !, l ^ -dihydroxy - ^ - methyl ^ O-chloroprost - ^ - enoic acid methyl ester produced:

IR (liquid film): ν = 3400 and 1740 cm "¹; NMR (CDCl3 solution): δ = 5.50-5.30 (2H, m), 4.50 (IH, m), 3.63 (3H, s) _t 3.48 (2H, t) and 0.95 (3H, d).

(c) (5Z, 13E) - (9a, IIIa, 15S) -6,9-epoxy-II, 15-dihydroxy-15- [3- (2-chloroethyl) -cyclopentyl] -16,17,18,19 , 20-pentanorprosta-5,13-dienoic acid methyl ester j 15- [3- (2-chloroethyl) -cyclopentyl] -16,17,18,19,20-pentanor-PGI ₂ -methylester 1 with the following physical characteristics is derived from according to example 1 (c) obtained (l3E) - (5RS, 6RS, 9a, lla, 15S) -5-iodo-6,9-epoxy-ll, 15-dihydroxy-15- [3- (2-chloroethyl) cyclopentyl] -16,17,18,19,20-pentanorprost-13-enoic acid methyl ester prepared: ■ '.

DSC (mobile phase diethyl ether / acetone = 3: 1 with 0.1 % triethylamine / using a silica gel plate pretreated with 5% triethylamine solution in diethyl ether): Rf = 0.4; IR (chloroform solution): ν = 3400, 1740, 1700 and 980 cm "¹; NMR (CDCl ₃ - + ■ benzene solution): δ = 5.7-5.4 (2H, m), 4.7-4.45 (IH, m), 4.35-3.3 (5H, m) and 3.65 (3H, s).

909836/0623

fs

EXAMPLE 3 ''

(l5E) - (5 RS _f 6RS, 9a, lla, 15S) -5-bromo-6 _> 9-eT) oxy-ll, 15-cLihv-

droxy- ^ O-chloroprost- ^ - enoic acid methyl ester

The solution of 175 mg of (5Z, 13E) - (9a, lla, 15S) -9, ll, 15-trihydroxy-20-chloroprosta-5 * 13-dienoic acid methyl ester [according to example 4 of British patent application no 090/75 and e.g. the equivalent
Belgian patent specification No. 842 113] in 3 ml
a mixture of chloroform and tetrahydrofuran (1: 1) with 85 mg of N-bromosuccinimide and stirred for 10 minutes at room temperature. It is diluted with ethyl acetate, washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate,
concentrated under reduced pressure and purified the residue
by column chromatography over silica gel using cyclohexane / ethyl acetate (1: 2) as the eluent, giving 165 mg of the title compound with the following physical
Characteristic values receives:

DSC (mobile phase ethyl acetate): Rf = 0.55;
IR (liquid film): ν = 3400, 1720 and 980 cm "¹;
NMR (CDCl3 solution): δ = 5 * 62-5.45 (2H, m), 4.66-4.38
(IH, m), 3.68 (3H, s), 3.55 "(2H, t) and 2.75 (3H, s).
EXAMPLE 4

(5Z, 13E) - (9a, lla, 15S) -6,9-epoxy-ll, 15-dihydroxy-20-chloroprosta-5,13-dienoic acid methyl ester (20-chloro-PGIpmethylester)

The solution of 50 mg prepared according to Example 3 (13E) - (5RS, 6RS, 9a _f lla, 15S) - is added under nitrogen.

909836/0623

-X-

5-bromo-6,9-epoxy-ll, 15-dihydroxy-20-chloro prost-13-enoic acid methyl ester in 0.2 ml of toluene with 0.1 ml of DBU .. The mixture is stirred for 1 hour at 50 ⁰ C, then 1.5 Hours at 70 ^° C. and then cools down to ⁰ ° C. The reaction mixture is admixed with 0.5 ml of 1N hydrochloric acid and 0.5 ml of phosphate buffer solution (pH 6.86) ^{while cooling to 0 ° C.} It is extracted rapidly with diethyl ether, the extract is dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue is purified by column chromatography over Florisil using ethyl acetate / n-hexane (1: 1) containing 0.1% triethylamine as the eluent, whereby one 15 mg of the title compound with the following physical characteristics is obtained:

DSC (mobile phase diethyl ether / acetone = 3: 1 with 0.1 % triethylamine, using a silica gel plate pretreated with 5 vol .- ^ iger triethylamine solution in diethyl ether): Rf = 0.52;

IR (liquid film): ν = 3400, 1740, 1700 and 980 cm "¹; NMR (CDCl ^ solution): δ = 5.61-5.40 (2H, m), 4.69-4.47 ( IH, m), 4.24-3.90 (2H, m), 3.66 (3H, s), 3.62 (IH, d), 3.53 (2H, t) and 2.33 (2H , t).

909836/0623

The scope of the present invention also includes pharmaceutical compositions which contain at least one new therapeutically useful compound of the general formula II or a cyclodextrin clathrate or, if R in formula II represents a hydrogen atom, a non-toxic salt thereof, or, if R represents a group

η 6 6 7

-CLEL-, H "~ ₇ , in which n, R and R have the meaning given above

n dJLL \ j, / -

processing, stands, a non-toxic acid addition salt thereof together with a pharmaceutical carrier or coating contain. In clinical practice, the new compounds according to the invention are usually used parenterally administered vaginally or rectally.

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous Solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending media are Propylene glycol, polyethylene glycol, vegetable oils such as Olive oil and injectable organic esters such as ethyl oleate. These compositions can also excipients such as Preservatives, wetting agents, emulsifiers and dispersants contain. They can be used, for example, by filtering germs, by incorporating sterilizing agents sterilize in the compositions or by irradiation. They can also be obtained in a more sterile, solid form Compositions to be dissolved in sterile water or other sterile injectable medium immediately before use can be dissolved, produce.

90 98 36/0 623

2906693

Solid compositions for vaginal administration include pessaries in a manner known per se be formulated and contain one or more of the active ingredients.

Solid compositions for rectal administration include suppositories in a manner known per se be formulated and one or more of the "active ingredients." contain.

The percentage of active ingredient in the compositions according to the invention can be varied, provided that there is a proportion suitable as a dose for the desired therapeutic effect. Of course, several dosage units can be administered at approximately the same time. In general the preparations should usually contain at least 0.025% by weight of active ingredient if they are to be administered are determined by injection. The dose used depends on the desired therapeutic effect, the Route of administration and duration of treatment.

In adult humans, the individual dose is generally between 0.05 and 500 μg parenterally he administration for the treatment of high blood pressure, between 0.05 and 500 μg for parenteral administration for the treatment of disorders of the peripheral circulation and between 0.05 and 500 μg for parenteral administration for the prevention and treatment of brain thrombosis, myocardial infarction and arteriosclerosis.

909836/0623

The following example explains pharmaceutical compositions according to the invention. EXAMPLE 5

(5Z, 13E) - (9ct, lla, 15S, l6RS) -6,9-Epo3cy-ll, 15-dihydroxy-ie-methyl-ZO-chlorprosta ^, Ij5-dienoic acid methyl ester (500 μg) is dissolved in ethanol (5 ml). Thereafter sterilize the solution by running it through a germ filter and fill 0.1 ml portions into 1 ml ampoules, which is 10 μg (5Z, 13E) - (9a> lla, 15S, l6RS) -6,9-epoxy-ll, lS-dihydroxy-lS-methyl-ZO-chloroprosta-S »13 ~ dienoic acid methyl ester per ampoule results. The ampoules are melted shut. To a suitable volume, e.g. diluted with 1 ml of Tris-HCl buffer solution (pH 8.6) gives the Contents of one ampoule one for administration by injection ready-to-use solution.

909836/0623

Claims (1)

EXPECTATIONS 1 »^ rostaglandin — I ₂ dialogues of the general formula II OH [where Y is ethylene or trans-vinylene, R is a hydrogen atom, a straight chain or branched alkyl group with 1 to 12 carbon atoms, an aralkyl group of 7 to Carbon atoms, one optionally by at least one straight-chain or branched alkyl group with 1 to 4 carbon atoms substituted cycloalkyl group with 4 to 7 carbon atoms, one optionally with at least one Chlorine atom or a trifluoromethyl group, straight-chain or branched alkyl group with 1 to 4 carbon atoms or Phenyl group substituted phenyl group, a 4 /
-C Hp COOR group (where m is an integer from 1 to 12 4th
and R is a straight or branched chain alkyl group to 4 carbon atoms), a -C HpOR group (where η is an integer from 2 to 12 and R " ^{3 is} a water 90S83ß / n623 atom or a straight-chain or branched alkyl group with 1 to 4 carbon atoms) or one _R 6
~ ^C n ^H 2n ^N \ 7 ~ ^Gru PP ^e (where η has the meaning given above fi 7 and R and R can be the same or different and each represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms), R for a hydrogen atom or a methyl or ethyl group, X for a -CH ₂ group (where ρ is an integer means from 2 to 8) Q x- * s, Q or a -R - (ι (CHp) group (where R is a simple bond) "R
dung or a straight-chain or branched alkylene group with 1 to 4 carbon atoms, R is a single bond or a straight-chain or branched alkylene group with 1 to 8 carbon atoms and q is an integer from 3 to 6) and Rr is a chlorine or fluorine atom which wavy line emanating from the carbon atoms in the 11- and 15-position denotes the α- or ß-configuration or mixed configuration and the double bond between C ₁ - and Cg is Z] and cyclodextrin clathrates of such acids and esters and, if R stands for represents a hydrogen atom, their non-toxic salts and, if R is _R 6 6 7 a -C ₁ Ji ₀ N """group in which n, R and R 'have the above Xi. ^ Xl ^ v ^ rr have given meaning, their non-toxic acid addition salts . 2. prostaglandin analogs according to claim 1, characterized in that R is a straight-chain or branched one Alkyl group having 1 to 4 carbon atoms. 3. prostaglandin analogs according to claim 1 or 2, 909836/0623 characterized in that R stands for methyl. 4 »Prostaglandin analogs according to claim 1, 2 or 2
3, characterized in that R stands for a hydrogen atom. 5 »prostaglandin analogs according to any one of the preceding claims, characterized in that Y for trans-vinylene. 6φ prostaglandin analogs according to one of the preceding claims, characterized in that X stands for a -CH ₂ group, where ρ has the meaning given in claim 1. 7 »Prostaglandin analogs according to claim 6, characterized in that a tetramethylene group optionally substituted by a methyl group is present _{as the -CH 2 _ group.} 8. prostaglandin analogs according to any one of claims 1 to 5? characterized in that X represents a -R -f (CH ₂ ) group, where R is a single bond ^ \ 9 or a straight-chain or branched alkylene group with 1 to 4 carbon atoms, R is a single bond or a straight-chain or branched alkylene group having 1 to 8 carbon atoms and q represents an integer from 3 to 6. 9 · Prostaglandin analogs according to claim 8, characterized in that characterized in that R represents a single bond. 10. prostaglandin analogs according to claim 8 or 9, 909836/0823 characterized in that q stands for 3 or 4. 11. prostaglandin analogs according to claim 8, 9 or 10, characterized in that R stands for a straight chain Alkylene group having 1 to 3 carbon atoms. 12. prostaglandin analogs according to any one of the preceding claims, characterized in that the to the Carbon atoms C-II and C-15 in that depicted in claim 1 General formula II bonded hydroxyl groups are in the α-configuration. 13. (5Z, 13E) - (9a, lla, 15S, 16RS) -6,9-epoxy-ll, 15-dihydroxy-16-methyl-20-chloroprosta-5,13-dienoic acid methyl ester. 14. (5Z, 13E) - (9a, lla, 15R) -6,9-epoxy-ll, 15-dihydroxy-15-C1- (4-fluorobutyl) -cyclobutyl] -16.17 »18.19 _f 20 -pentanorprosta-5,13-dienoic acid methyl ester. 15. (5Z, 13E) - (9a, IIIa, 15S, 17R) -6,9-epoxy-II, 15-dihydroxy-17-methyl-20-chloroprosta-5,13-dienoic acid methyl ester. 16. (5Z, 13E) - (9a, IIIa, 15S) -6,9-Epoxy-II, 15-dihydroxy-15- [3- (2-chloroethyl) -cyclopentyl] -16,17,18,19, 20-pentanorprosta-5,13-dienoic acid methyl ester. 17. (5Z, 13E) - (9a, IIIa, 15S) -6,9-epoxy-II, 15-dihydroxy-20-chloroprosta-5-13-dienoic acid methyl ester. 18. Cyclodextrin clathrate of a prostaglandin analog according to one of claims 1 to 17. 19. Non-toxic salts of a prostaglandin analog according to one of claims 1 and 4 to 12. 909836/0623 20 * Process for the preparation of prostaglandin analogs of the general formula II depicted in claim 1, in which the double bond between C ₁ - and Cg is Z and the various symbols have the meanings given in claim 1, characterized in that a compound of the general formula: III where R stands for a bromine or iodine atom, the absolute configurations at C ₅ and Cg are (5S, 6S) or (5R, 6R) or a mixture thereof (5RS, 6RS) and the other symbols have the meaning given in claim 1 , dehydrohalogenated. 21. The method according to claim 20, characterized in that if R in the general formula III depicted in claim 20 stands for a bromine atom, the dehydrohalogenation is carried out using a bicycloamine or an alkali metal alcoholate having 1 to 4 carbon atoms * 22ο method according to claim 20 _s characterized by '909836/0823 indicates that if R in the depicted in claim 20-. th general formula III stands for an iodine atom, dehydrohalogenation using a bicycloamine or an alkali alcoholate with 1 to 4 carbon atoms, peroxide, carbonate, hydroxide, benzoate, acetate, trifluoroacetate or bicarbonate, silver acetate or Tetramethylammonium peroxide takes place. 23 · The method according to claim 21 or 22, characterized in that 1,5-diazabicyclo [5 »4.0Jundec en-5 ₃ 1,5-diazabicyclo [4,3,0] nonene-5 or 1,4- Diazabicyclo [2.2.2] octane and the alkali metal alcoholate is a sodium or potassium alcoholate having 1 to 4 carbon atoms. 24. The method according to any one of claims 20 to 23, characterized in that the reaction is carried out in the range from room temperature to ⁰ C UO. 25. Procedure according to one of the. Claims 21 to 24, characterized in that if the reagent is a bicycloamine, the reaction in the absence of an inert one organic solvent or in the presence of toluene or benzene or, if the reagent of a bicycloamine is different, takes place in the presence of an inert organic solvent. 26. The method according to any one of claims 20 to 25, characterized in that one subsequently created Prostaglandin analogous to the general formula II, in which R stands for a hydrogen atom and the other symbols 909836/0623 -jit.-. _s have the meaning given above by methods known per se into a corresponding ester of that formula in which R is different from a hydrogen atom and the other symbols have the abovementioned meaning, are converted «■. 27 »The method according to any one of claims 20 to 26, characterized in that a Prostaglandin-analogously to the general formula II converted into a cyclodextrin clathrate thereof. 28. The method according to any one of claims 20 to 25, characterized in that a prostaglandin-analogue of the general formula II, in which R stands for a hydrogen atom according to known ones Methods converted into a non-toxic salt thereof. 29 · Method according to one of Claims 20 to 25, characterized in that a Prostaglandin analog of the general formula II, in which 1 R fi 7 R represents a group -C _n H _2n N ^ γ, in which n, R and R 'have the meaning given in claim 1, and the other symbols have the meaning given in claim 1, according to methods known per se in a not -toxic acid addition salt transferred from it. 30. Pharmaceutical compositions, characterized in that they contain at least one prostaglandin analog as the active ingredient according to one of claims 1 to 17 or a cyclodextrin clathrate thereof or, if R is in the general Formula II represents a hydrogen atom 909836/0623 non-toxic salt thereof or, if R in the general formula II depicted in claim 1 for a r6 6 7 ' Group ~ ^ _ΐ ^ -Ρΐ ^ \ 'T ^ ⁿ ^ ^{er n} * ^ ^{un (} ^ ^ ^e ^ ⁿ An ^s P ^ruc k have the meaning given, contains a non-toxic acid addition salt thereof together with a pharmaceutical carrier or coating . 31. Pharmaceutical compositions according to claim 30, characterized in that they are used as the active ingredient at least one prostaglandin analog according to one of Claims 13 to 17 or a cyclodextrin clathrate thereof together with a pharmaceutical carrier or coating. 32. Compounds of the general formula :. COOR ¹ wherein R has the meaning given in claim 20 and the other symbols have the meaning given in claim 1. 909836/0623